Fig. 13.1.

Regulatory mechanisms of TRPML1 channel activity. TRPML1 channel agonists such as PI(3,5)P2 and ML-SA1 may induce the opening of this channel. TRPML1 channel blockers such as PI(4,5)P2 or ML-SI1 may block this channel. In response to stimuli such as FasL and ET-1, CD38 converts NADP⁺ to NAADP that may activate the TRPML1 channel. PKA and mTORC1 are responsible for the phosphorylation of the TRPML1 channel which may result in dysfunction of this channel. Ca²⁺ released through the TRPML1 channel activates calcineurin (Cn) which is responsible for the dephosphorylation of TFEB. Dephosphorylated TFEB translocates to the nucleus to initiate the transcription of lysosomal and autophagic genes. Sphingolipids have different effects on TRPML1 channel activity, with inhibition by sphingomyelin (SM), no effect from ceramide (Cer), and enhancement by sphingosine (Sph). Cathepsin B mediates the critical or final cleavage of TRPML1 channel which results in dysfunction of this channel. The effects of oxidants on the TRPML1 channel remain controversial